1. Field of the Invention
The present invention generally concerns magnetic resonance spectroscopy (MRS) as it has been applied in radiological diagnostics for examination of biochemical and metabolic processes in the human body (called “in vivo spectroscopy”). The present invention in particular concerns improvements in MRS data acquisition methods as well as apparatuses for implementation of such methods wherein a polarization transfer is used for signal amplification of difficult-to-detect atomic nuclei types.
2. Description of the Prior Art
Like magnetic resonance tomography (MRT), magnetic resonance spectroscopy (MRS) is based on the phenomenon of magnetic resonance (discovered in 1946) that was first used in basic research to measure the magnetic properties of nuclei. Only when it was observed in the 1960's that the magnetic resonance signal (MR signal) of a nucleus is also influenced by its chemical environment and that this “chemical shift” can be used to characterize chemical substances, did “high resolution MR” in vitro become established. This has been successfully in physical, chemical, biochemical and pharmaceutical research, and compositional for analysis and structural analysis of complex macromolecules.
In the early 1980's it was discovered that the magnetic resonance signal, due to its dependency on the chemical environment (water tissue or fatty tissue), represents the basis for a medical non-invasive imaging technique that, as magnetic resonance tomography (MRT), to date represents one of the most important radiological examination modalities in medicine.
It was also recognized that the imaging signals in magnetic resonance tomography additionally provide chemical information that can be evaluated for examination of biochemical reactions and of metabolic processes in the living body. This was designated spatially-resolved spectroscopy on the living organism or “in vivo spectroscopy” in the living organ or “clinical magnetic resonance spectroscopy” (MRS) in contrast to the “high-resolution MR” in vitro, which normally ensues in the laboratory and thus in contrast to pure imaging magnetic resonance tomography (MRT).
The physical bases of magnetic resonance are briefly explained in the following:
The subject (patient or organ) to be examined is exposed to a strong, constant magnetic field both in MRS and in MRT. The nuclear spins of the atoms in the subject, which were previously randomly oriented, thereby align, causing discrete energy states to arise. Radio-frequency energy can now produce transitions between these energy levels. For example, if an equal occupation of the states is achieved by a radio-frequency pulse, an induced signal can thus be detected by the reception coil after the deactivation of the exciting RF field. The measurement subject can be selectively excited and the signals can be spatially coded by the use of non-homogeneous magnetic fields generated by gradient coils.
The acquisition of the data in MRS ensues in the time domain. The acquisition of MRT data ensues in k-space (frequency space domain). The MR spectrum in the frequency domain, and the MRT image in the image domain, are linked with the measured data by means of Fourier transformation.
A volume excitation in the subject thus ensues by means of slice-selective radio-frequency pulses with simultaneous application of gradient pulses. For the excitation of a cuboid in MRS, three slice-selective radio-frequency pulses are applied in three orthogonal spatial directions. These are normally three sinusoidal, Gaussian or hyperbolic RF pulses that are radiated into the subject to be examined simultaneously with rectangular or trapezoidal gradient pulses. The radiation of the RF pulses ensues via one or more RF antennas.
By the combination of the aforementioned pulses a frequency spectrum in the range of the resonant frequency that is specific for a nucleus type is radiated into the (normally cuboid) region of the subject to be examined. The respective nuclei in the selected (excited) region (volume of interest, VOI) respond by emitting electromagnetic signals that are detected in the form of a sum signal (free induction decay signal, FID signal) or in the form of a (half), echo signal, such as a spin echo signal, in a special acquisition mode of the RF antennas. The analog signal (FID or echo) is sampled by switching of an ADC (analog-digital converter), digitized and stored in a storage unit, or is Fourier-transformed, so that a “spectrum” can be shown on a visualization unit (monitor).
The two components of the measured (FID or echo) signal describe the projections of the temporal oscillation behavior (already known as Lamor precession of the nuclear magnetization vector M in the x-y plane of a stationary reference system (laboratory coordinate system).
The temporal decay of the signal is determined by the T2 weighted transverse relaxation (spin-spin relaxation). The transverse relaxation leads to the subsidence of the time-dependent transverse magnetization Mxy(t), while the T2 time (more precisely called the T2* time, which, according to the equation
                                          1                          T              2              *                                =                                    1                              T                2                                      +                          γ              ⁢                                                          ⁢              Δ              ⁢                                                          ⁢                              B                0                                                    ,                            (        1        )            takes into account local B0 field inhomogeneities ΔB0) determines the decay of the FID or echo signal as a characteristic time constant. γ is the gyromagnetic ratio, which is the energetic coupling constant of the respective nucleus at the external magnetic field and is an invariable constant of the respective nucleus type.
The complex and time-dependent (thus three-dimensional) FID or echo signal itself is the electromagnetic response to one or more previously-radiated, circularly-polarized radio-frequency excitation pulses into the substance or into the tissue to be examined.
If the substance contains only a single nucleus type (for example protons in pure water) and if the RF excitation pulse radiates with a frequency that exactly corresponds to the Lamor frequency of the protons (63.8 MHz at 1.5 Tesla), the measured FID or echo signal of the water protons contains no harmonic/periodic components (sinusoidal and cosinusoidal components) since in a rotating (at 63.8 MHz) reference system no precession rotation of the transversal magnetization occurs. (The relative movement in the rotation direction is equal to zero). Only the relaxation-dependent exponential decay of the transversal magnetization vector, which represents a non-modulated exponential function (dashed curve in FIG. 2A), is measurable.
If the radiated RF excitation pulse exhibits a frequency that does not exactly correspond to that of water protons (for example 63.8 MHz+400 Hz), an excitation of the protons will still occur due to the pulse width, but the measured FID or echo signal (given a reference frequency for the data acquisition equal to the frequency of the RF pulse) contains a harmonic of a 400 Hz component that, according to FIG. 2A, is modulated to the exponential relaxation decay
      e                  -        t                    T        2        *              .
In the general case, the substance or the subject to be examined (in medical in vivo spectroscopy) will contain not just one nucleus type (1H, 31P, 13C) but rather a multiple of nucleus types to be analyzed. Moreover, the nuclei of the same nucleus type will exhibit different resonances (Lamor frequencies) relative to one another due to their different bonding in different molecules (different chemical environment) and can differ as what are known as metabolites.
In (in vivo) proton spectroscopy the resonance range of the signals is 10 ppm (parts per million) at approximately 63.8 MHz, the spectral width for (in vivo) phosphor spectroscopy lies at 26 MHz at approximately 30 ppm, and for (in vivo) 13C spectroscopy the resonances are distributed in the spectra across a range of 200 ppm at approximately 16 MHz (these specifications apply for 1.5 Tesla). The specification of the resonance frequency change δ relative to the system frequency (RF center frequency v0) in ppm, thus in millionths of the resonance frequency according to the equation
                              δ          =                                                                      v                  Substance                                -                                  v                  0                                                            v                0                                      ·                          10              6                                      ,                            (        4        )            is independent of the magnetic field strength.
In the general case, the FID or echo signal thus represents a temporally-dependent response signal—“signal representation in the time domain”—with an exponential curve in which all resonances (ωx, xεN) of the excited nuclei in the respective-metabolites are modulated superimposed and frequency-coded.
An FID signal that (according to FIG. 2A) contains the frequency response of only a single metabolite, supplies only one resonance line according to FIG. 2B.
An FID signal that contains the frequency responses, as an example, of three different metabolites is shown in FIG. 3A. It can be seen that the FID or echo signal in FIG. 3A is coded in a significantly more complex manner than the FID or echo signal of FIG. 2A, which exhibits only one frequency. The components can be separated (extracted) by a Fourier transformation and can be sorted according to their respective resonance frequencies, so that according to FIG. 3B a three-component spectrum is obtained with resonance lines at ω0, ω1 and ω2.
The Fourier-transformed result of the FID or echo signal (FIGS. 2B, 3B) is generally designated as a spectrum, also called a “signal representation in the frequency domain”.
As already mentioned, the gyromagnetic ratio γ (equation (1)) is an invariable constant of the respective atomic nucleus type (for example for the proton γ/2π=42.577 MHz/T), and with a constant external magnetic field slightly different resolution frequencies are considered in MR data in which the examined atomic nuclei are integrated into different molecules. The electrons in the molecule that participate in the chemical bond are responsible for this. They shield the external magnetic field such that the atomic nucleus “sees” different magnetic fields (BK) depending on the bond type, which is caused by the already-mentioned slight shift of the respective resonant frequency and is known as a “chemical shift δK”:BK=B0−δKB0  (5)
A number of resonance lines that can be associated with individual molecule groups often occur in a molecule complex. According to equation (4), the chemical shift is for the most part quantitatively specified in ppm relative to a reference line (v0).
Aside from the chemical shift, one often also still observes a fine division of the nuclear magnetic resonance lines in the form of multiplet lines (doublets, triplets, quartets etc.). The magnetic interaction (spin-spin coupling) between the nuclei is responsible for this. This interaction is not transferred directly into the spectrum, but rather indirectly via the electrons of the chemical bond. For analysis of spectra with fine structure one typically uses the energy function (Hamilton operator Ĥ) with the interaction energy Jkl (scalar energy coupling constant) between the various spin states Ĵk and Ĵl
                              H          ⋒                =                              -                          ∑                              γ                ⁢                                                                  ⁢                ℏ                ⁢                                                                  ⁢                                                      B                    0                                    ⁡                                      (                                          1                      -                                              δ                        k                                                              )                                                  ⁢                                                      J                    ⋒                                    zk                                                              +                                    ∑                              k                ,                l                                      ⁢                                          J                kl                            ⁢                                                J                                      ⇀                    ⋒                                                  k                            ⁢                                                J                                      ⇀                    ⋒                                                  l                                                                        (        6        )            the eigenvalues and eigenfunctions of which must describe the measured spectrum corresponding to the adopted molecule model. The structure of (macro-) molecules is identifiable in this manner in physical chemistry and biochemistry. In medicine, typical metabolites can be detected non-invasively in vivo using their spectrum.
The low sensitivity with regard to magnetic resonance in protons and other nuclei (for example 19F, 203Tl, 205Tl, 31P) with relatively large magnetic moments thereby no longer represents a problem due to the achievable high magnetic field strength of modern MR apparatuses. All other MR-active atomic nuclei types (with the exception of 3H) are even less MR-sensitive than the cited nuclei, so detectability thereof is more difficult due to low natural occurrence and long relaxation times, which is why methods for detection improvement or signal amplification in (in vivo) MR are of high importance.
A known class of methods for detection improvement of weakly-sensitive atomic nuclei in MR spectroscopy is based on the phenomenon known as polarization transfer, in which the high population difference of two or more energy levels that is dominant (standard) for a sensitive nucleus is transferred to the spin system of a coupled, insensitive nucleus by spin-spin coupling.
The principle of polarization transfer-based detection improvement is explained in detail in the following:
In a simplified manner, a two-spin system composed of a sensitive nucleus and an insensitive nucleus (for example 1H and 13C) is considered.
In a magnetic field B0, such nuclei (quantum spin number ½) can respectively adopt two discrete energy states. The change of such an energy level is associated with absorption or emission of a quantumω=ΔE=γB0  (7)
The occupation of the energy level in the external magnetic field B0 ensues according to the Boltzmann statistic
                                          N            q                                N            p                          =                              ⅇ                                          Δ                ⁢                                                                  ⁢                E                            kT                                ≈                      1            -                                          γ                ⁢                                                                  ⁢                ℏ                ⁢                                                                  ⁢                                  B                  0                                            kT                                                          (        8        )            
The result is an excess of nuclear magnetic moments aligned parallel to the magnetic field B0.
The gyromagnetic ratio γ of the appertaining nucleus (which changes its spin alignment given the transition Ep→Eq) is decisive for the occupation difference (population difference) between two states Eq and Ep. A greater population difference results for states that belong to the transitions of a sensitive nucleus type A (large γ) than for those that belong to the transitions of an insensitive nucleus type X (small γ).
The population in the term scheme (energy level diagram) of such an AX system composed of a strongly sensitive nucleus (A) and a weakly sensitive nucleus (X) is schematically shown in FIGS. 4A, 4B and 4C.
If exchanging the appertaining spin populations is achieved by a (selective) population inversion for an A line (A1 or A2) in the MR spectrum, the term scheme of FIG. 4B applies, that shows amplified absorption (X1) and amplified emission (X2) for the X transitions, and the term scheme of FIG. 4C applies, wherein X1 shows amplified emission and X2 shows amplified absorption. In both cases (FIGS. 4B, 4C) the population equilibrium is disturbed via selective population inversion between the states (1) and (3) or between the states (2) and (4).
The prior population difference, decisive for the sensitive nucleus and corresponding to the signal intensity, now applies for the insensitive nucleus. This phenomenon is known as polarization transfer, which is used for signal amplification of NMR-insensitive atomic nuclei.
Of most general interest is the sensitivity improvement in 1H-coupled spectra of insensitive nuclei, such as, for example, 13C (but also 15N or 29Si), thus the intensity increase for XAn spin systems with A=1H and X=13C.
The energy level diagram of a CH spin system (n=1) with different coupling is shown in FIGS. 5A, 5B and 5C.
FIG. 5A shows the four energy levels 1, 2, 3 and 4 that are possible based on different C-H spin adjustments without coupling to the external magnetic field B0, meaning that J=0 applies for the scalar energy coupling constant. Since in this case the 1H transitions 3→1 and 4→2, and the 13C transitions 2→1 and 4→3 are equally energetic, only an 1H line and a 13C line respectively result in the spectrum (no division and no hyper-fine structure).
The system behaves differently in FIGS. 5B and 5C, in which an energetic coupling of the C-H spin states ensues, whereby in the case of FIG. 5B the energy level of the parallel spin states (↑↑, ↓↓) is increased by J/4 and that of the antiparallel spin states (↑↓, ↓↑) is decreased by J/4. In the case of FIG. 5C, the system behaves precisely opposite. The coupling by ±J/4 results from the relationγ1H≈4γ13C  (9)and leads in each case to respectively two energetic, different transitions of the respective atomic nucleus type, which respectively leads to a two-fold fine structure division in the spectrum, meaning respectively to two immediately adjacent spectral lines in the form of a doublet. Each nucleus species (type) thereby separately experiences a total energy change of J.
In order to calculate the population ratios (relative population or transition probabilities) relevant for the polarization transfer and thus for the respective signal amplification to be achieved, it is reasonable to consider the diagrams of FIGS. 4A and 4C more precisely, i.e. quantitatively (see FIGS. 6A, 6B, 6C).
In FIG. 6A the lowermost energy level possesses an energy of
            1      2        ⁢          γ      H        +            1      2        ⁢          γ      C      (this is proportional to the population probability) while the other energy levels have (in increasing order) energies or, population probabilities of
                                                        1              2                        ⁢                          γ              H                                -                                    1              2                        ⁢                          γ              C                                      ,                                                  -                          1              2                                ⁢                      γ            H                          +                              1            2                    ⁢                      γ            C                              and
            -              1        2              ⁢          γ      H        -            1      2        ⁢          γ      C      corresponding to the respective coupled spin states (αα=↑↑=parallel to B0), (αβ=↑↓), (βα=↑↓), (ββ=↓↓=antiparallel to B0).
After a suitable (spin) preparation of the system by radiation of suitable electromagnetic radio-frequency pulses in the framework of a defined pulse sequence, targeted energy can be supplied to the system, such that the αβ coupling changes (flips) into the energetically higher ββ coupling. After the preparation, the system thus has spin-spin pairs parallel (αα=↑↑) and antiparallel (ββ=↓↓) to the B0 field.
For simplicity, if the constant energy amount of
            1      2        ⁢          γ      H        +            1      2        ⁢          γ      C      is added to the energy level, the energy states γH+γC, γH, γC and 0 are obtained. If the relative ratio of the nuclear sensitivities of 1H and 13C (γH=4 and γC=1), is also considered relative values of 5, 4, 1 and 0 result for the energy levels according to FIG. 6B. These values likewise correspond (as already mentioned) to the relative population probabilities or the relative populations since the magnetic moment μ characterizing the sensitivity defines both the differences of the energy levels and the population probabilities (according to Boltzmann).
As can be seen from FIG. 6B, the population difference of the 13C transitions in the non-excited system is relatively low (Δ=1−0=+1; Δ=5−4=+1). The 13C doublet accordingly has a low MR sensitivity in comparison to the 1H doublet. If the system is now forced into a higher energy state (alignment of the spin pairs anti-parallel to B0) via energy transfer, population differences of 13C transitions arise that produce an emission amplification of Δ=1−4=−3 as well as an absorption amplification of Δ=5−0=+5 in the spectrum (FIG. 6C).
This signal amplification of an X-doublet in the MR spectrum (for example X=13C) is shown in FIG. 7A. The unit of the ordinate is arbitrary. What is important is the clear amplification of the two X-doublet lines.
The expansion to a 3-atom AX spin system (for example to a CH2 group) leads to a much more complex term scheme and (as can be shown) to an X-triplet with the relative intensities (1)-(2)-(1) in the spectrum (FIG. 7B). A signal amplification leads to values of (−7)-(2)-(9) in this system.
The intensity increase that is obtained for the general expansion to AnX spin systems (A=1H, X=13C) can be determined according to FIGS. 8A and 8B by comparison with a Pascal triangle.
Shown are line number and relative intensities for an X-multiplet of an AnX group (A=1H) given Boltzmann distribution (FIG. 8A) as well as after population inversion (FIG. 8B). The respective triangle is obtained by (combinatorial analysis) of the (whole-number) energy level transitions of the underlying term scheme.
The preparation of the spin system and therewith the achievement of polarization transfer can ensue using different RF pulse sequences. Best known is the INEPT method (Insensitive Nuclei Enhanced by Polarization Transfer, Morris, Freeman, J. Am. Chem. Soc. 101, 760-762 (1979)).
Further methods are, for example, refocused INEPT, DEPT (Distortionless Enhancement by Polarization Transfer), SINEPT, etc.
As is later explained in detail, all of these methods are generally based on the simultaneous application (radiation) of RF pulses at the different frequencies of the involved nucleus types (thus, for example, 1H, 13C). A disadvantage of this approach is that MR apparatuses that are not able to simultaneously emit at the various frequencies of the involved nuclei are not able to implement MR data acquisitions with polarization transfer.